The general goal of the projected research is to arrive at an understanding of the mode of action of glucocorticoids at molecular and cellular levels and at the level of the whole organism. Central to our investigations will be an intensive study of the mechanisms of cortisol action on rat thymus lymphocytes in vitro. Actions of glucocorticoids on lymphoid tissue are of great importance owing to their applications in the treatment of lymphocytic leukemias and in immunosuppression, and because they provide the most striking example of the general catabolic actions of glucocorticoids on peripheral tissues. Our work will be based on our previous studies showing that thymus cells respond directly to glucocorticoids in vitro. This response appears to be effected through protein receptors that react specifically with hormone molecules to form complexes that become bound in the nucleus, apparently initiating synthesis of RNA which in turn gives rise to synthesis of a protein that inhibits glucose transport. Inhibition of glucose transport is the earliest general metabolic effect of glucocorticoids that has been identified, and probably is responsible in large part for the catabolic effects. We propose to study intensively the various steps in this overall process, from the initial glucocorticoid-receptor interaction to the eventual manifestation of the hormone effect as an inhibition of glucose transport.